1

Mary L. Bouxsein, PhD

Beth Israel Deaconess Medical CenterHarvard Medical School, Boston, MA

mbouxsei@bidmc.harvard.edu

UCSF Osteoporosis CourseJune 2013

Beyond BMD:

Bone Quality andBone Strength

Disclosures

Consultant / advisor:Amgen, Eli Lilly, Merck

Research funding:Amgen, Merck

Outline

• Determinants of Bone Strength

• Limitations of BMD

• Beyond BMD

• Biomechanics of Fractures: Comparing applied loads to strength

Structural failure of the skeleton

2

Design of a Structure

• Consider what loads it mustsustain

• Design options– Overall geometry– Building materials– Architectural details

Determinants of Whole Bone StrengthMorphologysize (mass)shape (distribution of mass)porositymicroarchitecture

Properties of Bone Matrixmineralizationcollagenmicrodamage…others…

Bouxsein, Osteop Int, 2003

Hierarchical Structure of Bone

Cell nanometer

Matrix100’s nanometer

LamellarOsteonal

micron

µ-architecture

micron to 100’s micron

Whole Bone

millimeter andbeyond

Assessing BoneBiomechanical Properties

DISPLACEMENT

LOAD

StructuralProperties

MaterialProperties

3

Biomechanical TestingKey Properties

DISPLACEMENT

LOAD

Strength

Energy absorbed (toughness)

Stiffness

Mechanical Behavior of Common Materials

Plastic(ductile)

Glass (brittle)

Deformation (Strain)

Load(Stress)

Mechanical Behavior of Bone and Its Constituents

Bone

Collagen

Mineral

Strain

Stress

Outline

• Osteoporosis & Bone Strength

• Limitations of BMD

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Clinical Assessment of Bone Strength

Areal BMD by DXA• Bone mineral / projected area (g/cm2)• Reflects (indirectly)

– Bone size– Mineralization

• Moderate to strong correlation withwhole bone strength (r2 = 50 - 90%)

• Strong predictor of fracture risk inuntreated women (Marshall et al, 1996) Bouxsein et al, 1999

Hip BMD T-score (SD)-3 -2 -1 0 1

0

10

20

50

60

70

80Age (yrs)

10 Y

ear F

ract

ure

Prob

abili

ty (%

)

Kanis et al, 2004

Age and BMD Are Independent Risk Factors for HipFracture

> 5-fold increase infracture probabilityfrom age 50 to 80

History of Previous Fracture is a Risk Factor for Future Fracture,Independent of BMD

0 1 2 3 4 5 6

Vert Frx

No Vert Frx

5.83.4

2.3

1.71.0

0.2

Risk of Vertebral Fractures (% / yr)

Ross et al, Ann Int Med, 1991

LowMiddleHigh

BMD Tertiles

* Based on WHO guidelines for Osteoporosis Diagnosis

Fracture risk prediction:Less than half of patients who fracture have

osteoporosis by BMD testing(ie t-scores > -2.5*)

• Only 34% of women and 21% of men suffering a non-vertebralfrx had BMD in osteoporotic range (Schuit et al, 2004; 2006)

• Only half of elderly women with incident hip frx had BMD inosteoporotic range at baseline (Wainwright et al , JCEM 2005)

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Outline

• Osteoporosis & Bone Strength

• Limitations of BMD

• Beyond BMD

Bone Strength

MORPHOLOGYsize & shape

microarchitecture

MATRIX PROPERTIESmineralizationcollagen traits

etc…

OSTEOPOROSIS DRUGS

Bouxsein, Best Practice in Clin Rheum, 2005

BONE REMODELINGformation / resorption

Bone Strength

MORPHLOGYsize & shape

microarchitecture

MATRIX PROPERTIEStissue compositionmatrix properties

BONE REMODELINGformation / resorption

Distribution of Mass Affects MechanicalBehavior

Moment of Inertiaproportional to d4

d

6

Effect of cross-sectional geometry onlong bone strength

↑

↑↑↑

↑

↑↑

=

=

Compressive Strength

Bending Strength

===aBMD (by DXA)

Bone Strength

SIZNE & SHAPEmacroarchitecturemicroarchitecture

MATRIX PROPERITEStissue compositionmatrix properties

BONE REMODELINGformation / resorption

Age-Related Changes in Trabecular Microarchitecture

Decline in bone massand deterioration of

trabecular bonestructure both

contribute to decreasedbone strength.

Excessive Bone Resorption Weakens TrabecularArchitecture

Perforation

Stress concentration(focal weakness)

L. Mosekilde, 1998

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Effect of Resorption Cavities on Trabecular BoneStrength

van der Linden, et al, JBMR 2001

20% decrease in bone mass

1) trabecular thinning↓

30% decrease in strength

2) add resorption cavities

↓ 50% decrease in strength

Effect of Density Reduction on Strength:Change in Trabecular Thickness vs. Number

Density Reduction (%)

Residual Strength

(%)

5 10 150

25

50

75

100

0

Silva and Gibson, Bone, 1997

TrabecularThickness

TrabecularNumber

20% reductionin strength

65% reductionin strength

Microarchitectural changes thatinfluence bone strength

Force required to cause aslender column to buckle:

• Directly proportional to– Column material– Cross-sectional geometry

• Inversely proportional to– (Length of column)2

Force

Mosekilde, Bone, 1988

L

Theoretical effect of cross-struts on bucklingstrength

Buckling Strength proportional to (Strut Length)2

# Horizontal Effective Buckling Trabeculae Length Strength

0 L S

1 1/2 L 4 x S

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Dramatic Changes in Trabecular Architecture in EarlyPostmenopausal Women

Dufresne TE et al. Calcif Tissue Int. 2003;73:423-432.

Baseline 1 yr

(52 yr old woman, 3 yrs post-menopause)

Anti-Resorptive Tx Preserves Trabecular Architecture in EarlyPostmenopausal Women

(Placebo vs Risedronate, 5 mg/d, 1 yr)

*P<0.05 vs baseline.†P< 0.05 vs PBO.

PBO (n=12)

Trabecularnumber

Trabecularseparation

Trabecularbone volume

–3.3 *

–20.3*

–13.5 *

13.1 *

0

5

10

15

% c

hang

e fr

om b

asel

ine

SpineBMD

5

1015

20

Dufresne TE et al. Calcif Tissue Int. 2003; 73:423-432.

RIS (n=14)

2.0 *

15.2

6.4

–7.2

†

†

†

†

20 yr old 80 yr old

Age-related changes in femoral neck cortex andassociation with hip fracture

Those with hip fractures have:

• Preferential thinning of the inferior anterior cortex• Increased cortical porosity

Bell et al. Osteop Int, 1999; Jordan et al. Bone, 2000

Mayhew et al, Lancet 2005

Porosity is profound inthe aging femoral neck

Bousson et al, JBMR, 2004

19 elderly femalecadavers (87 ± 8 yrs)

Intracortical porosityranged from 5% to 39%

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Cortical porosity and trabecularization of theendocortical surface with age

Zebaze et al, Lancet 2010

29 yr

67 yr

90 yr

Bone loss (mg/HA)CorticalTrabecular

Cortical bone lossincreases with age.

Prior studies have likelyunderestimated cortical

bone loss

50-64 65-79 > 80 yrs

Bone Strength

GEOMETRYmacroarchitecturemicroarchitecture

MATERIALtissue compositionmatrix properties

BONE REMODELINGformation / resorption

How is mineralization density influenced by rate ofbone turnover?

• Slow process of 2o

mineralization

• Decreased boneturnover allowsmineralization toproceed

Primarymineralization

(3 months)

Secondarymineralization

(years)

Time

Degree ofMineralization (%)

100-

50 -

0 -

Increased bone turnover with estrogen deficiencydecreases mineralization density

Meunier and Boivin,Bone, 1997

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Relationship between mineralization andbiomechanical properties

Normal

Low(osteomalacia)

High(osteopetrosis)

Displacement

Load

Mineralization

Stiffness Strength

Toughness

Bone remodeling & microdamage

What is “damage” ?

– Repetitive loading

– No repair process– ↓ Mechanical properties

Microdamage in Bone

• Associated with decreased cortical bonestrength

• Microcracks seen in human femur & vertebra,increase with age

• Signal for remodeling & repair– in animals, microdamage increases when

remodeling is suppressed

• No demonstrated relationship with fracturerisk

Schaffler, 1995; Wenzel et al, 1996; Mashiba et al, 2001; Burr et al 1997, 2002; Arlot et al 2008

Fazzalari et al, Bone, 1998

Human femoral neck

Age-related changes in bone properties thatlead to decreased bone strength

• Decreased bone mass and BMD

• Altered geometry

• Altered architecture

– Cortical thinning– Cortical porosity– Trabecular deterioration

• Altered matrix propertiesImages from L. Mosekilde, Technology andHealth Care. 1998

young

elderly

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Whole bone strength declinesdramatically with age

0

2000

4000

6000

8000

10000 Femoral Neck(sideways fall)

young

old

Courtney et al, J Bone Jt Surg 1995; Mosekilde L. Technology and Health Care. 1998.

Lumbar Vertebrae(compression)

Who

le B

one

Stre

ngth

(New

tons

)

0

2000

4000

6000

8000

10000

young old

Outline

• Determinants of Bone Strength

• Limitations of BMD

• Beyond BMD

• Biomechanics of Fractures: Comparing applied loads to strength

Fracture Etiology

FRACTURE?

Loads applied to the bone

Bone StrengthΦ = Applied Load

Failure Load

FRACTURE?

Loads applied to the bone

direction & magnitude

Bone strengthGeometry

MicrostructureMaterial Properties

Fall traitsProtective responsesSoft-tissue padding

Impact surface

Propensity to fall

Bending, lifting activity

Spine curvatureMuscle strength

Disc degeneration

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Biomechanics of HipFracture

• Over 90% of hip fx’s associated with a fall

• Less than 2% of falls result in hip fracture

• Fall is necessary but not sufficient

• What is a high risk fall ?

Independent Risk Factors for Hip Fx

Factor Adjusted Odds Ratio

Fall to side 5.7 (2.3 - 14)↓ Femoral BMD 2.7 (1.6 - 4.6)*↑ Fall energy 2.8 (1.5 - 5.2)**↓ Body mass index 2.2 (1.2 - 3.8)*

* calculated for a decrease of 1 SD** calculated for an increase of 1 SD

Greenspan et al, JAMA, 1994

Estimating Loads Applied to the Hip

In young volunteers, only 2/6 wereable to break the fall

85% of impact force delivereddirectly to femur

Force ↑ by ↑ body wt

Force ↓ by ↑ thickness oftrochanteric soft tissue

Peak impact forces applied to greater trochanter:270 - 730 kg (600 - 1600 lbs)

(for 5th to 95th percentile woman)Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996

Peak impact forces applied to greater trochanter:270 - 730 kg (600 - 1600 lbs)

(for 5th to 95th percentile woman)Robinovitch et al, 1991; 1997; van den Kroonenberg et al 1995, 1996

Very high forces appliedto the hip during a

sideways fall

• Human cadavers• Human volunteers• Crash dummy• Mathematical models and

simulations

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Femoral ‘strength’ depends on loading direction

Stance Sideways Fall

Femur is weak in atypical loading conditions

Keyak et al, J Biomechanics, 1998

0123456789

Stance Sideways Fall

Failu

re L

oad

(kN

)

P < 0.0013.4-fold lower

2318 ± 300 N7978 ± 700 N

0

2000

4000

6000

8000

10000

Fem

ur S

tren

gth

(New

tons

)

Young(age = 33)

Old(age = 74)

Courtney et al, J Bone Jt Surg 1995

Load duringsideways fall}

Femoral strength in sideways falldeclines markedly with age

Older femurs are half as strongand absorb 1/3 as much energyas young femurs

Biomechanics of Vertebral Fractures

• Difficult to study– Many do not come to clinical

attention– Slow vs. acute onset– The event that causes the fracture is

often unknown

• Poor understanding of the relationshipbetween spinal loading and vertebralfragility

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Estimating Loads on the Spine

Biomechanical model• Simulate bending and lifting activities• Height, weight, body position

• Determine compressive forces onvertebra for different activities

Φ = Applied LoadFailure Load

Standing 51

Rise from chair 173

Stand, hold 8 kg, 230arms extended

Stand, flex trunk 30o, 146arms extendedLift 15 kg from floor 319for a 162 cm, 57 kg woman

Activity Load (% BW)

Predicted Loads on Lumbar Spine for Activitiesof Daily Living

Ratio of load to strength for L3 during activities ofdaily living

Adapted from Myers and Wilson, Spine, 1997

1.5

2.6 1.1 0.7

2.1 0.9

3.7 1.5 1.0 0.7

3.0 1.3 0.8

1.1

1.4

1.4

0.6 0.4 0.3 0.2 0.2

0.5 0.4 0.3

0.6 0.4 0.3 0.3

0.6 0.5

0.6 0.5 0.4

0.5 0.3 0.2 0.2 0.1

0.6 0.4 0.3 0.2 0.2

0.6 0.4 0.3 0.2 0.2

Get up from sitting

Lift 15 kgknees straightLift 15 kg w/deep knee bendLift 30 kgknees straightLift 30 kg w/deep knee bendOpen windoww/ 6 kg of forceOpen windoww/ 10 kg of forceTie shoessitting down

-3.5 -2.8 -2.2 -1.5 -0.8 0

Lateral Spine BMD t-score

Applied LoadBone Strength

Fracture PreventionStrategies

Reduce the Loads Applied to Bone– Decrease fall frequency / severity– Safe-landing strategies– Trochanteric padding– Avoid high risk lifting / bending activities

Maintain or Increase Bone Strength– Exercise, diet (Ca, Vit D), pharmacologic treatment

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Summary: Factors Affecting Bone Strength andFracture Risk

Microarchitecture

Size & Shape LoadingMaterial